Tuberous sclerosis (TSC)
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Written | 2002-06 | Julie Steffann, Arnold Munnich, Jean-Paul Bonnefont |
INSERM U393, Groupe Hospitalier Necker-Enfants Malades, Tour Lavoisier 2, 149 rue de Sövres, 75743 Paris Cedex15, France |
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1. Identity
Other names | Bourneville disease |
Epiloia | |
Atlas_Id | 10014 |
Genes implicated in | TSC1 TSC2 |
Inheritance | First genetic cause of epilepsy associated with mental retardation = epiloia. 2/3 of cases are sporadic, 1/3 are inherited. Somatic mosaicism has been reported in association with a milder form of the disease. Germinal mosaicism has been described and must be taken into account for genetic counselling. |
2. Clinics
Note | Disability in TSC patients most often results from the involvement of brain. Two types of lesions are static (hamartias) ; cortical tubers, and subcortical heterotopic nodules, whereas subependymal nodules are often progressive (hamartoma), hence the term subependymal giant cell astrocytoma. |
Phenotype and clinics | The definition of the tuberous sclerosis complex requires either two major features or one major feature plus two minor features. - Facial angiofibromasor forehead plaque - Non traumatic ungual or periungual fibroma - Hypomelanotic macules (three or more) - Shagreen patch ( connective tissue nevus) - Multiple retinal nodular hamartomas - Cortical tuber - Subependymal nodule - Subependymal giant cell astrocytoma - Cardiac rhabdomyoma, single or multiple - Lymphangiomyomatosis - Renal angiomyolipoma - Multiple, randomly distributed pits in dental enamel - Hamartomatous rectal polyps - - Bone cysts - Cerebral white matter radial migration lines - Gingival fibromas - Nonrenal hamartoma - Retinal achromic patch - " confetti " skin lesions - Multiple renal cysts |
Neoplastic risk | |
3. Cytogenetics
Inborn conditions | Increased frequency of premature centromere disjonction (PCD) in cultured fibroblasts, especially for chromosome 3 |
Cytogenetics of cancer | No special feature |
4. Genes involved and Proteins
Note | Two genes are involved, TSC1 and TSC2. The patients with TSC1 mutations would have a milder form of the disease, compared to those with TSC2 mutations. |
Gene Name | TSC1 (Tuberous Sclerosis 1) |
Location | 9q34.13 |
Note | Accounts for about 50% of TSC patients |
DNA/RNA | |
Description | 23 exons |
Protein | |
Note | Tumor suppressor |
Description | Hamartin and tuberin cohybridize in vivo. Hamartin is a growth inhibitory protein, affecting cell proliferation via deregulation of G1 phase, possibly by regulating cellular adhesion through ezrin-radixin-moiesin family proteins and the small GTP-binding protein RHO |
Gene Name | TSC2 (tuberous sclerosis 2) |
Location | 16p13.3 |
Note | Accounts for about 50% of TSC patients. |
DNA/RNA | |
Description | 41 exons |
Protein | |
Note | tumor suppressor |
Expression | Fonctions as a GTPase activating protein which activates the Ras-related family of small GTP-binding proteins such as Rap1 and Rab5. Inhibits the G1/S transition and promotes entry to the G0 phase. The Eker rat, a naturally occuring animal model of TSC, has an autosomal dominant trait of renal cell carcinoma caused by a germline mutation in the rat TSC2 gene. |
Mutations | |
Germinal | Most TSC1 and TSC2 mutations are truncating mutations. Both large deletions and missense mutations are not uncommon at TSC2 locus, whereas most TSC1 mutations are small truncating lesions. |
Somatic | Loss of heterozygosity has been described in some tumor types, such as angiomyolipomas, giant cell astrocytomas, or rhabdomyomas, but is rare in cortical tubers. |
5. Bibliography
Complete inactivation of the TSC2 gene leads to formation of hamartomas. |
Au KS, Hebert AA, Roach ES, Northrup H |
American journal of human genetics. 1999 ; 65 (6) : 1790-1795. |
PMID 10577937 |
The natural history of cardiac rhabdomyoma with and without tuberous sclerosis. |
Bosi G, Lintermans JP, Pellegrino PA, Svaluto-Moreolo G, Vliers A |
Acta paediatrica (Oslo, Norway : 1992). 1996 ; 85 (8) : 928-931. |
PMID 8863873 |
Apparent preferential loss of heterozygosity at TSC2 over TSC1 chromosomal region in tuberous sclerosis hamartomas. |
Carbonara C, Longa L, Grosso E, Mazzucco G, Borrone C, Garrè ML, Brisigotti M, Filippi G, Scabar A, Giannotti A, Falzoni P, Monga G, Garini G, Gabrielli M, Riegler P, Danesino C, Ruggieri M, Magro G, Migone N |
Genes, chromosomes & cancer. 1996 ; 15 (1) : 18-25. |
PMID 8824721 |
Molecular genetic advances in tuberous sclerosis. |
Cheadle JP, Reeve MP, Sampson JR, Kwiatkowski DJ |
Human genetics. 2000 ; 107 (2) : 97-114. |
PMID 11030407 |
Comprehensive mutation analysis of TSC1 and TSC2-and phenotypic correlations in 150 families with tuberous sclerosis. |
Jones AC, Shyamsundar MM, Thomas MW, Maynard J, Idziaszczyk S, Tomkins S, Sampson JR, Cheadle JP |
American journal of human genetics. 1999 ; 64 (5) : 1305-1315. |
PMID 10205261 |
A germline insertion in the tuberous sclerosis (Tsc2) gene gives rise to the Eker rat model of dominantly inherited cancer. |
Kobayashi T, Hirayama Y, Kobayashi E, Kubo Y, Hino O |
Nature genetics. 1995 ; 9 (1) : 70-74. |
PMID 7704028 |
Neuropathology of tuberous sclerosis. |
Mizuguchi M, Takashima S |
Brain & development. 2001 ; 23 (7) : 508-515. |
PMID 11701246 |
Tuberous Sclerosis Consensus Conference: recommendations for diagnostic evaluation. National Tuberous Sclerosis Association. |
Roach ES, DiMario FJ, Kandt RS, Northrup H |
Journal of child neurology. 1999 ; 14 (6) : 401-407. |
PMID 10385849 |
High rate of mosaicism in tuberous sclerosis complex. |
Verhoef S, Bakker L, Tempelaars AM, Hesseling-Janssen AL, Mazurczak T, Jozwiak S, Fois A, Bartalini G, Zonnenberg BA, van Essen AJ, Lindhout D, Halley DJ, van den Ouweland AM |
American journal of human genetics. 1999 ; 64 (6) : 1632-1637. |
PMID 10330349 |
6. Citation
This paper should be referenced as such : |
Steffann, J ; Munnich, A ; Bonnefont, JP |
Tuberous sclerosis (TSC) |
Atlas Genet Cytogenet Oncol Haematol. 2002;6(4):314-315. |
Free journal version : [ pdf ] [ DOI ] |
On line version : http://atlasgeneticsoncology.usal.es/classic/Tumors/TuberSclerosID10014.html |
7. External links
OMIM | 191092 |
OMIM | 191100 |
Orphanet | Tuberous sclerosis |
MeSH | D014402 |
MedGen | D014402 |
UMLS | C0041341 |
ICD-10 | Q85.1 |
HGMD | 120466 |
REVIEW articles | automatic search in PubMed |
Last year articles | automatic search in PubMed |
© Atlas of Genetics and Cytogenetics in Oncology and Haematology | indexed on : Wed Nov 28 16:25:37 CET 2018 |
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